Dry eye is one of the most frequently diagnosed ocular diseases affecting more than 5 million people in the United States alone. Dry eye is s a multi-factorial disease, resulting from a common etiology of insufficient tear film causing ocular surface damage and symptoms of ocular discomfort. The few current therapies available, which include immunosuppressive agents and over-the-counter tear replacements, are not sufficiently efficacious for many users or only provide transient relief from dry eye symptoms. Therefore, the development of novel agents to treat dry eye would be of tremendous benefit to the therapeutic milieu. The volume of tear film on the ocular surface represents a balance between tear fluid output versus fluid loss via drainage, evaporation, or epithelial absorption. Similar to other epithelial tissues, the epithelium of the conjunctiva and cornea are capable of regulating the hydration status of the mucosal surface through active salt and water transport. The epithelial sodium channel (ENaC) is a key regulator of sodium (and water) absorption in numerous tissues including the eye. The inhibition of ENaC in the eye is predicted to preserve lacrimal secretions and maintain hydration on the ocular surface. Parion Sciences has developed a novel series of compounds that specifically and potently inhibit ENaC, which are predicted to be good candidate molecules for clinical development for the treatment of dry eye. In proof-of-concept studies, Parion compounds produce a concentration-dependent increase in tear output that persists for greater than 8 hours in normal mice and rats. Furthermore, Parion compounds significantly increase tear output and are associated with improved corneal staining in a dry eye mouse model. Taken together, these data suggest that the Parion compounds are excellent candidates for clinical development. Prior to the initiation of a clinical program it is essential that a lead molecule be chosen and validated in a human model system. Parion's ENaC blocker library contains >500 novel compounds and identifying a lead candidate with the longest duration of action is critical to the success of Parion's dry eye program. In this proposal we outline a series of studies that will assist Parion in the selection of the most promising lead compounds to advance towards clinical development. PUBLIC HEALTH RELEVANCE: Keratoconjunctivitis sicca (KCS) or chronic dry eye disease (DED) is one of the most frequently diagnosed ocular diseases, resulting in painful irritation of the eye and impaired vision. KCS/DED often results from inadequate aqueous tear fluid on the eyes. Parion Sciences is developing a novel therapeutic agent that is predicted to provide long acting relief from dry eye symptoms.